Publisher Summary This chapter presents various developments in antitussive therapy. Cough is a f... more Publisher Summary This chapter presents various developments in antitussive therapy. Cough is a forceful defensive reflex maneuver that leads to expulsion of irritants, fluids, mucus, or foreign material from the respiratory tract. The reflex triggers a complex, multiphasic motor pattern characterized by sequential coordination of large increases in motor output to an array of inspiratory and expiratory skeletal muscles. Centrally active antitussive agents act preferentially by depressing the cough center at the level of the lower brainstem without affecting peripheral sensory or motor endplate effector responses. Antitussive agents may also act in the periphery to inhibit the sensory impulses that lead to the activation of the cough reflex. Activation of the NK 1 and NK 2 receptors by endogenous tachykinins has been associated with a variety of pathological conditions affecting the lung and bronchi including plasma extravasation, bronchoconstriction and cough. In addition to their central activity, neurokinin antagonists can also act at peripheral sites. NK 1 and NK 2 antagonists inhibit the proinflammatory, bronchoconstrictor and rapidly adapting receptors (RAR) stimulation activity of sensory tachykinins by a blocking action at the level of the effector cell.
We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR ... more We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.
The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are disc... more The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.
... In 1 : 1 dioxanemethylene chloride at 40 for 6 hr afforded cleanly the same con jugated enone... more ... In 1 : 1 dioxanemethylene chloride at 40 for 6 hr afforded cleanly the same con jugated enone 16, UVmax 228 nm,1 which was clearly distinguished from the 15keto derivative of PGF2 methyl ester (UVm 232 am ... 2. EJ Corey and N. Raju, Tetrahedron Letters, 24, 5571 (1983). ...
The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing i... more The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound ) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3()-thiomethyl pyrrolidine analog . Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate suitable for twice daily oral dosing as a potential new cancer therapeutic.
Bioorganic & medicinal chemistry letters, Jun 15, 2018
Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity ... more Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100 nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10 mpk = 0 μM h; F% = 0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10 mpk = 26 μM h; F% = 70).
Bioorganic & medicinal chemistry letters, Aug 15, 2017
Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroa... more Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood (hWBA). However, lead compound 2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound.
We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors contai... more We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub-nanomolar potency (Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series.
N 0-(Ethoxymethylene)hydrazinecarboxylic acid methyl ester was synthesized in one step in good yi... more N 0-(Ethoxymethylene)hydrazinecarboxylic acid methyl ester was synthesized in one step in good yield. This reagent was successfully applied to the one-pot synthesis of 4-substituted 2,4-dihydro-3H-1,2,4-triazolin-3-ones from readily available primary alkyl and aryl amines. This reaction process is relatively mild and easy to carry out. It is especially useful for the formation of sterically hindered triazolinones, which are otherwise difficult to obtain via existing literature procedures. A possible mechanistic pathway for the transformation is outlined.
Identification of a Novel 1'-[5-((3,5-Dichlorobenzoyl)methylamino)-3-(3,4-dichlorophenyl)-4-(meth... more Identification of a Novel 1'-[5-((3,5-Dichlorobenzoyl)methylamino)-3-(3,4-dichlorophenyl)-4-(methoxyimino)pentyl]-2-oxo-(1,4'bipiperidine) (I) as a Dual NK 1 /NK 2 Antagonist.
The Journal of pharmacology and experimental therapeutics, 2003
We present the pharmacological and pharmacokinetic profiles of a novel histamine H3 receptor anta... more We present the pharmacological and pharmacokinetic profiles of a novel histamine H3 receptor antagonist, N-(3,5-dichlorophenyl)-N'-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). The H3-receptor binding Ki values for SCH 79687 were 1.9 and 13 nM in the rat and guinea pig (GP), respectively. The Ki values for SCH 79687 at histamine H1 and H2 receptors were greater than 1 microM. SCH 79687 showed a 41- and 82-fold binding selectivity for the H3 receptor over alpha 2A-adrenoceptors and imidazoline I2, and >500-fold H3 selectivity compared with over 60 additional receptors. The pA2 value for SCH 79687 in the GP ileum electrical field-stimulated (EFS) contraction was 9.6 +/- 0.3. Similar H3 antagonist activity was observed in the EFS cryopreserved and fresh tissue isolated human saphenous vein (HSV) assays (pKb = 9.4 +/- 0.3 and 10.1 +/- 0.4). SCH 79687 (30 nM) did not block clonidine-induced inhibition of EFS-induced contractions in HSV. SCH 79687 (ED50 = 0.3 mg/kg ...
The structural modification of the benzylic ether region of oxime 1 has resulted in the identific... more The structural modification of the benzylic ether region of oxime 1 has resulted in the identification of several novel aryl amides as selective or dual NK1/NK2 antagonists.
Two diversity-driven asymmetric syntheses of a potent NK1 receptor antagonist 1 were achieved. Th... more Two diversity-driven asymmetric syntheses of a potent NK1 receptor antagonist 1 were achieved. These syntheses provided two complementary approaches that were well positioned for further modifications of several different sites of medicinal chemistry interests in the NK1 structural motifs. The de novo piperidine ring construction approach delivered key intermediates that were best suited for piperidine C4 and C5 SAR investigations.
A short, high yielding, enantioselective synthesis of the novel H 3 agonist Sch 50971 1 is descri... more A short, high yielding, enantioselective synthesis of the novel H 3 agonist Sch 50971 1 is described. The key enantiodifferentiating step is the 1,4-addition of a chiral N-propionyloxazolidinone to a nitroolefin.
An efficient and practical synthesis of sterically hindered N-substituted lactams has been develo... more An efficient and practical synthesis of sterically hindered N-substituted lactams has been developed starting from simple starting materials. The stereochemistry of the synthetically useful N,N acetal intermediate has been established.
Publisher Summary This chapter presents various developments in antitussive therapy. Cough is a f... more Publisher Summary This chapter presents various developments in antitussive therapy. Cough is a forceful defensive reflex maneuver that leads to expulsion of irritants, fluids, mucus, or foreign material from the respiratory tract. The reflex triggers a complex, multiphasic motor pattern characterized by sequential coordination of large increases in motor output to an array of inspiratory and expiratory skeletal muscles. Centrally active antitussive agents act preferentially by depressing the cough center at the level of the lower brainstem without affecting peripheral sensory or motor endplate effector responses. Antitussive agents may also act in the periphery to inhibit the sensory impulses that lead to the activation of the cough reflex. Activation of the NK 1 and NK 2 receptors by endogenous tachykinins has been associated with a variety of pathological conditions affecting the lung and bronchi including plasma extravasation, bronchoconstriction and cough. In addition to their central activity, neurokinin antagonists can also act at peripheral sites. NK 1 and NK 2 antagonists inhibit the proinflammatory, bronchoconstrictor and rapidly adapting receptors (RAR) stimulation activity of sensory tachykinins by a blocking action at the level of the effector cell.
We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR ... more We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.
The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are disc... more The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.
... In 1 : 1 dioxanemethylene chloride at 40 for 6 hr afforded cleanly the same con jugated enone... more ... In 1 : 1 dioxanemethylene chloride at 40 for 6 hr afforded cleanly the same con jugated enone 16, UVmax 228 nm,1 which was clearly distinguished from the 15keto derivative of PGF2 methyl ester (UVm 232 am ... 2. EJ Corey and N. Raju, Tetrahedron Letters, 24, 5571 (1983). ...
The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing i... more The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound ) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3()-thiomethyl pyrrolidine analog . Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate suitable for twice daily oral dosing as a potential new cancer therapeutic.
Bioorganic & medicinal chemistry letters, Jun 15, 2018
Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity ... more Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100 nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10 mpk = 0 μM h; F% = 0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10 mpk = 26 μM h; F% = 70).
Bioorganic & medicinal chemistry letters, Aug 15, 2017
Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroa... more Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood (hWBA). However, lead compound 2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound.
We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors contai... more We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub-nanomolar potency (Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series.
N 0-(Ethoxymethylene)hydrazinecarboxylic acid methyl ester was synthesized in one step in good yi... more N 0-(Ethoxymethylene)hydrazinecarboxylic acid methyl ester was synthesized in one step in good yield. This reagent was successfully applied to the one-pot synthesis of 4-substituted 2,4-dihydro-3H-1,2,4-triazolin-3-ones from readily available primary alkyl and aryl amines. This reaction process is relatively mild and easy to carry out. It is especially useful for the formation of sterically hindered triazolinones, which are otherwise difficult to obtain via existing literature procedures. A possible mechanistic pathway for the transformation is outlined.
Identification of a Novel 1'-[5-((3,5-Dichlorobenzoyl)methylamino)-3-(3,4-dichlorophenyl)-4-(meth... more Identification of a Novel 1'-[5-((3,5-Dichlorobenzoyl)methylamino)-3-(3,4-dichlorophenyl)-4-(methoxyimino)pentyl]-2-oxo-(1,4'bipiperidine) (I) as a Dual NK 1 /NK 2 Antagonist.
The Journal of pharmacology and experimental therapeutics, 2003
We present the pharmacological and pharmacokinetic profiles of a novel histamine H3 receptor anta... more We present the pharmacological and pharmacokinetic profiles of a novel histamine H3 receptor antagonist, N-(3,5-dichlorophenyl)-N'-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). The H3-receptor binding Ki values for SCH 79687 were 1.9 and 13 nM in the rat and guinea pig (GP), respectively. The Ki values for SCH 79687 at histamine H1 and H2 receptors were greater than 1 microM. SCH 79687 showed a 41- and 82-fold binding selectivity for the H3 receptor over alpha 2A-adrenoceptors and imidazoline I2, and >500-fold H3 selectivity compared with over 60 additional receptors. The pA2 value for SCH 79687 in the GP ileum electrical field-stimulated (EFS) contraction was 9.6 +/- 0.3. Similar H3 antagonist activity was observed in the EFS cryopreserved and fresh tissue isolated human saphenous vein (HSV) assays (pKb = 9.4 +/- 0.3 and 10.1 +/- 0.4). SCH 79687 (30 nM) did not block clonidine-induced inhibition of EFS-induced contractions in HSV. SCH 79687 (ED50 = 0.3 mg/kg ...
The structural modification of the benzylic ether region of oxime 1 has resulted in the identific... more The structural modification of the benzylic ether region of oxime 1 has resulted in the identification of several novel aryl amides as selective or dual NK1/NK2 antagonists.
Two diversity-driven asymmetric syntheses of a potent NK1 receptor antagonist 1 were achieved. Th... more Two diversity-driven asymmetric syntheses of a potent NK1 receptor antagonist 1 were achieved. These syntheses provided two complementary approaches that were well positioned for further modifications of several different sites of medicinal chemistry interests in the NK1 structural motifs. The de novo piperidine ring construction approach delivered key intermediates that were best suited for piperidine C4 and C5 SAR investigations.
A short, high yielding, enantioselective synthesis of the novel H 3 agonist Sch 50971 1 is descri... more A short, high yielding, enantioselective synthesis of the novel H 3 agonist Sch 50971 1 is described. The key enantiodifferentiating step is the 1,4-addition of a chiral N-propionyloxazolidinone to a nitroolefin.
An efficient and practical synthesis of sterically hindered N-substituted lactams has been develo... more An efficient and practical synthesis of sterically hindered N-substituted lactams has been developed starting from simple starting materials. The stereochemistry of the synthetically useful N,N acetal intermediate has been established.
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